Britta Siegmund

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (202)884.2 Total impact

  • BMC Gastroenterology 12/2015; 15(1). DOI:10.1186/s12876-015-0292-4 · 2.11 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555299 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555241 · 1.67 Impact Factor
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    ABSTRACT: Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over-expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-γ treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor α and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-κB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
    Journal of Cellular and Molecular Medicine 06/2015; DOI:10.1111/jcmm.12595 · 3.70 Impact Factor
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    ABSTRACT: Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease. © Georg Thieme Verlag KG Stuttgart · New York.
    Zeitschrift für Gastroenterologie 05/2015; DOI:10.1055/s-0034-1399400 · 1.67 Impact Factor
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    ABSTRACT: Macrophages are key players in inflammatory bowel diseases (IBD). This study aimed to determine site-specific effects of defined macrophage subtypes on the integrity of the intestinal epithelial barrier. Macrophage subtypes in situ in intestinal specimens of patients with IBD were visualized by immunohistochemistry. In vitro polarization of human peripheral CD14 cells yielded M1 or M2 macrophages. The influence of primary monocytes or macrophage subtypes on epithelial barrier integrity was analyzed by transepithelial resistance measurements, Western blot analysis, confocal laser scanning microscopy, and cytometric bead array in a coculture model of primary human macrophages and layers of intestinal epithelial cell lines. The lamina propria of the inflamed intestine in patients with IBD, predominantly in Crohn's disease, is massively infiltrated by CD68 cells also positive for inducible nitric oxide synthase and tumor necrosis factor (TNF) α. The presence of M1 macrophage shifted the balance in the local macrophage compartment towards a proinflammatory state. In the coculture model, monocytes and M1 macrophages reduced transepithelial resistance as a marker for epithelial barrier integrity. The mechanisms for paracellular leakage included intracellular relocalization of tight junction proteins like claudin-2 and epithelial cell apoptosis. Determined by specific cytokine blockade, M1 macrophages exerted their deleterious effect mainly through TNF-α, whereas monocyte-mediated damage was driven by the inflammasome effector cytokines, interleukin-1β and interleukin-18. Lamina propria monocytes and M1 macrophages invading intestinal tissues directly contribute to disrupting the epithelial barrier through deregulation of tight junction proteins and induction of epithelial cell apoptosis, thus driving intestinal inflammation in IBD.
    Inflammatory Bowel Diseases 04/2015; DOI:10.1097/MIB.0000000000000384 · 5.48 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD)-like conditions in glycogen storage disease (GSD) type Ib have been predominantly described in children. Signs and symptoms of GSD type Ib are hypoglycemia, pancytopenia and hepatosplenomegaly. Based on few published cases, there is evidence that granulocyte-colony stimulating factor (G-CSF) in patients with glycogenosis-related pancytopenia might ameliorate the IBD-like disease through leukocyte increase. Here we firstly describe a case of an adult 33-year-old Caucasian male patient with GSD type Ib accompanied with IBD-like disease with persistent pancytopenia despite moderate-dose G-CSF treatment. Recent vomiting and abdominal discomfort were due to a high-grade stenosis in the transverse colon. A dose increase of the G-CSF successfully normalized his leukocyte count. However, the stenosis worsened and surgical therapy was needed. We suggest that symptomatic patients with GSD type Ib should undergo endoscopic examination in order to detect IBD-like disease and to initiate early treatment.
    BMC Gastroenterology 04/2015; 15(1):45. DOI:10.1186/s12876-015-0271-9 · 2.11 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-720-S-721. DOI:10.1016/S0016-5085(15)32456-2 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-328. DOI:10.1016/S0016-5085(15)31089-1 · 13.93 Impact Factor
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    ABSTRACT: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs.
    Oncotarget 03/2015; · 6.63 Impact Factor
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    ABSTRACT: IL-17-producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A-producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS (-/-) Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS (-/-) mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; DOI:10.4049/jimmunol.1401964 · 5.36 Impact Factor
  • Zeitschrift für Gastroenterologie 02/2015; 53(02):136-136. DOI:10.1055/s-0034-1397525 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 02/2015; 53(2):136-136. · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 02/2015; 53(2):136. · 1.67 Impact Factor
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    ABSTRACT: The cell adhesion molecule CD2 facilitates antigen-independent T-cell activation and CD2 deficiency or blockade reduces intestinal inflammation in murine models. We here aimed to evaluate the therapeutic potential of monoclonal antibodies (mAb) specific for human CD2 in colitis treatment. Transfer colitis induced by naϊve CD4+ T cells expressing human CD2 was treated with anti-human CD2 mAb. The mAb CB.219 protected from severe colitis in a preventive treatment regimen, while therapeutic treatment ameliorated intestinal inflammation. Diminished intestinal tissue damage was paralleled by a profound suppression of lamina propria lymphocytes to produce proinflammatory cytokines and tumor necrosis factor α as well as the neutrophil chemoattractant CXC motif ligand 1 and the CC chemokine ligand 3. Furthermore, infiltration with macrophages and T cells was low. Thus, reduced intestinal inflammation in our humanized colitis model by targeting CD2 on T cells with the mAb CB.219 suggests a novel approach for colitis treatment.
    Clinical Immunology 01/2015; 157(1). DOI:10.1016/j.clim.2015.01.004 · 3.99 Impact Factor
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    ABSTRACT: Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided. © Georg Thieme Verlag KG Stuttgart · New York.
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    ABSTRACT: Background: The p53 pathway is altered in gastroenteropancreatic neuroendocrine tumors, although mutations in the TP53 gene are rare events. However, aberrant activation of its negative regulators, caused e.g. by gene amplifications of the MDM2 gene are frequently observed. Therefore, we assessed MDM2 expression in a series of GEP-NEN fresh frozen material and studied the effects of MDM2 inhibition in human GEP-NEN cell lines. Materials and Methods: Fresh frozen tumor material of 35 gastroenteropancreatic neuroendocrine tumors was prospectively analyzed for MDM2 and p53 expression. Furthermore, the gastroenteropancreatic neuroendocrine cell lines BON, QGP-1, KRJ-1 and LCC18 were treated with Nutlin-3, a small molecule inhibitor of MDM2-p53 interaction. Treated cells were analyzed by WST-1 proliferation and apoptosis assays. In Western Blot analyses, fractioned lysates of nuclear and cytoplasmic proteins, as well as whole cell lysates were analyzed for p53 pathway protein expression and activation after Nutlin-3 treatment. TP53 Mutation analysis of the cell lines was performed to verify the druggability with Nutlin 3 in vitro. Results: MDM2 is strongly expressed in gastroenteropancreatic neuroendocrine tumors patient material and cell lines. MDM2 inhibitions lead to a decrease in cellular proliferation in vitro in p53 wild type cell lines. Further data concerning the association of MDM2 expression with clinical parameters, primary tumor localization and target gene expression will be presented on the meeting. Conclusion: MDM2 is involved in aberrant GEP-NEN signal transduction and a druggable target in p53 wild type cells, which merits further investigation.
    EORTC – NCI – AACR Symposium on Molecular Targets and Cancer Therapeutics, Barcelona; 11/2014
  • Uta Syrbe, Britta Siegmund
    Gut 11/2014; 64(7). DOI:10.1136/gutjnl-2014-308436 · 13.32 Impact Factor
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    Lea I Kredel, Britta Siegmund
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    ABSTRACT: Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier.
    Frontiers in Immunology 09/2014; 5:462. DOI:10.3389/fimmu.2014.00462

Publication Stats

3k Citations
884.20 Total Impact Points

Institutions

  • 2004–2015
    • Charité Universitätsmedizin Berlin
      • • Medical Department, Division of Hepatology and Gastroenterology
      • • Institute of Health Sciences Education and Nursing Science
      • • Department of Gastroenterology, Infectiology and Rheumatology
      • • Institute of Medical Informatics
      Berlín, Berlin, Germany
    • Mental Health Center of Denver
      Denver, Colorado, United States
  • 2008
    • St. Marien- und St. Annastiftskrankenhaus
      Ludwigshafen, Rheinland-Pfalz, Germany
  • 2002–2008
    • University of Colorado
      • • Division of Infectious Diseases
      • • Department of Medicine
      Denver, Colorado, United States
  • 2005
    • University Hospital of Lausanne
      • Institut universitaire de pathologie
      Lausanne, VD, Switzerland
  • 2003–2004
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 1997–2000
    • Ludwig-Maximilian-University of Munich
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine II
      München, Bavaria, Germany